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Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease

BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (F...

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Autores principales: Johnson, Lynne L., Johnson, Jordan, Ober, Rebecca, Holland, April, Zhang, Geping, Backer, Marina, Backer, Joseph, Ali, Ziad, Tekabe, Yared
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955479/
https://www.ncbi.nlm.nih.gov/pubmed/33327730
http://dx.doi.org/10.1161/JAHA.120.016696
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author Johnson, Lynne L.
Johnson, Jordan
Ober, Rebecca
Holland, April
Zhang, Geping
Backer, Marina
Backer, Joseph
Ali, Ziad
Tekabe, Yared
author_facet Johnson, Lynne L.
Johnson, Jordan
Ober, Rebecca
Holland, April
Zhang, Geping
Backer, Marina
Backer, Joseph
Ali, Ziad
Tekabe, Yared
author_sort Johnson, Lynne L.
collection PubMed
description BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose‐bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti‐RAGE antibody (CR‐3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent ((201)Tl) single‐photon emission computed tomography/x‐ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [(99m)Tc]dodecane tetra‐acetic acid–polyethylene glycol–single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR‐3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra‐acetic acid‐polyethylene glycol‐scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR‐3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher (201)Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR‐3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE‐blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR‐3 shows promise for clinical treatment in diabetic peripheral artery disease.
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spelling pubmed-79554792021-03-17 Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease Johnson, Lynne L. Johnson, Jordan Ober, Rebecca Holland, April Zhang, Geping Backer, Marina Backer, Joseph Ali, Ziad Tekabe, Yared J Am Heart Assoc Original Research BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose‐bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti‐RAGE antibody (CR‐3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent ((201)Tl) single‐photon emission computed tomography/x‐ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [(99m)Tc]dodecane tetra‐acetic acid–polyethylene glycol–single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR‐3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra‐acetic acid‐polyethylene glycol‐scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR‐3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher (201)Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR‐3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE‐blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR‐3 shows promise for clinical treatment in diabetic peripheral artery disease. John Wiley and Sons Inc. 2020-12-17 /pmc/articles/PMC7955479/ /pubmed/33327730 http://dx.doi.org/10.1161/JAHA.120.016696 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Johnson, Lynne L.
Johnson, Jordan
Ober, Rebecca
Holland, April
Zhang, Geping
Backer, Marina
Backer, Joseph
Ali, Ziad
Tekabe, Yared
Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title_full Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title_fullStr Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title_full_unstemmed Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title_short Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
title_sort novel receptor for advanced glycation end products‐blocking antibody to treat diabetic peripheral artery disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955479/
https://www.ncbi.nlm.nih.gov/pubmed/33327730
http://dx.doi.org/10.1161/JAHA.120.016696
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